MOST CLOSELY HLA MATCHED ALLOGENEIC VIRUS SPECIFIC CYTOTOXIC T-LYMPHOCYTES (CTL)

这个子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。次级项目的主要支助 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 表示子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 摘要 当患者接受造血干细胞移植（HSCT）时，如果供体是治疗血癌或其他血液疾病的最佳匹配者，他们就有感染的风险，直到他们能够从供体中生长出新的免疫系统。在此期间，他们可能发展为严重的病毒感染，其中Epstein巴尔病毒（EBV）、巨细胞病毒和腺病毒是三种最常见的可引起问题的病毒。研究人员先前已经证明，有可能从移植供体中培养出称为病毒特异性CTL的特殊T细胞，当它们被送回患者时，可以预防和治疗这些病毒感染。然而，培养这些细胞需要2-3个月的时间，因此对于每个感染这些病毒之一的患者来说，从移植供体中培养病毒特异性CTL并不是一个实际的选择。 在这项研究中，研究人员将看看是否有一种替代方法是从正常供体中制备病毒特异性CTL库，这些CTL可以冷冻储存，然后在移植后治疗受试者，如果他们发生这些病毒感染之一。 病毒特异性CTL系将从正常供体生长并冷冻。为了制造CTL细胞系，我们首先用一种特殊产生的腺病毒（一种载体）感染称为单核细胞的血细胞，这种腺病毒也携带巨细胞病毒（CMV）基因的一部分。这是一种禁用的病毒，一旦感染发生，它就无法复制自己，因此无法传播。 然后这些感染的单核细胞刺激T细胞对腺病毒和CMV做出反应，并杀死被这些病毒感染的细胞。然后，我们对T细胞进行第二次刺激，使用也被EBV感染的细胞（我们将在实验室中通过用EBV感染供体血液来制备），这样细胞现在可以识别三种病毒CMV，EBV和腺病毒。一旦我们制造了足够数量的T细胞，我们将对其进行测试，以确保它们杀死感染这些病毒的细胞并将其冷冻。 如果移植患者感染了这些病毒之一，并且尽管接受了标准治疗，感染仍然存在，他或她将有资格接受适当匹配的CTL系。 主要目的是确定该策略是否可行和安全。一个风险是，由于我们制造的T细胞与受体不完全匹配，它们可能会攻击受试者并引起一种称为移植物抗宿主病（GVHD）的疾病。我们将密切监测这种并发症。 次要目的是确定T细胞输注对病毒感染的影响，并观察接受者是否可以对这些病毒保持免疫。我们还将观察T细胞存活的时间。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT When patients undergo a hemopoietic stem cell transplant (HSCT) from a donor who is the best possible match to treat blood cancers or other blood diseases they have a risk of infection until they can grow a new immune system from the donor. During this period they may develop serious viral infections with Epstein Barr virus (EBV), cytomegalovirus and adenovirus being three of the most common viruses that can cause problems. Investigators have previously shown that it is possible to grow up special T cells called virus-specific CTLs from the transplant donor that can prevent and treat these viral infections when they are given back to the patient. However it takes 2-3 months to grow these cells so it is not a practical option to grow virus-specific CTLs from the transplant donor for every patient that gets an infection with one of these viruses. In this study, investigators will see if an alternative approach is to make banks of virus-specific CTLs from normal donors that could be stored frozen and then made available to treat subjects post transplant if they developed one of these viral infections. Virus-specific CTL lines will be grown from normal donors and frozen. To make the CTL lines we first infect blood cells called monocytes with a specially produced adenovirus (a vector) that also carries part of the Cytomegalovirus (CMV) gene. This is a disabled virus that cannot reproduce itself once infection has occurred so it cannot spread. These infected monocytes then stimulate the T cells to respond to adenoviruses and CMV, and kill the cells infected with these viruses. We then give a second stimulation to the T cells, using cells which are also infected with EBV (which we will make from donor blood by infecting them with EBV in the laboratory) so that the cells now recognize three viruses CMV, EBV and Adenovirus. Once we have made sufficient numbers of T cells we will test them to make sure they kill cells infected with these viruses and freeze them. If a transplant patient gets an infection with one of these viruses, and the infection persists despite standard therapy, he or she would be eligible to receive a suitably matched CTL line. The primary objective is to determine if this strategy is feasible and safe. One risk is that because the T cells we make are not a complete genetic (HLA) match for the recipient, they might attack the subject and cause a condition called graft versus host disease (GVHD). We will closely monitor for this complication. Secondary objectives are to determine the effects of the T cell infusion on the virus infection and to see if the recipients can stay immune to these viruses. We will also see how long the T cells survive.